Pyrrolo[2,1-c][1,4]benzodiazepine and indole conjugate (IN6CPBD) has better efficacy and superior safety than the mother compound DC-81 in suppressing the growth of established melanoma in vivo

Melanoma is one of the most chemo-resistant cancers. The remission rate of current therapy remains low. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of antitumor Antibiotics that binds to N2 of guanine to form a DNA adduct. However, significant cardiotoxicity hampers their clinical use. We have previously synthesized a PBD indole conjugate (IN6CPBD) that induced Apoptosis in several Cancer cell lines. The purpose of this study was to assess the efficacy and safety of the IN6CPBD for established murine melanoma cells in vivo. IN6CPBD induced more Apoptosis than DC-81 as evidenced by sub-G1 distribution, annexin V positivity, and decrease mitochondrial membrane potential (DeltaPsi(mt)). The melanomas were established in C57BL/6 mice by injecting B16F10 cells via the tail vein. Three courses of therapy were instituted after day 5 and the mice were sacrificed at day 20. The tumor growth rate in the foot pad was significantly reduced in IN6CPBD-treated mice than that in DC-81- and PBS-treated mice. The tumor burden in the lungs was also reduced significantly in IN6CPBD-treated mice accompanied with the most prominent TUNEL staining. Renal function, and cardiac enzymes were not altered significantly by IN6CPBD or DC-81, however, robust deterioration of liver function was noticed in the DC-81-treated mice. In summary, potent Apoptosis could be elicited by the PBD indole conjugate IN6CPBD, accompanied with a better efficacy and less liver function impairment than the mother compound DC-81 in treating established melanoma metastasis in vivo.